Molecular Pathways: Pathogenesis and clinical implications of microbiome alteration in esophagitis and Barrett’s esophagus Running Title: Alteration of microbiome in esophagitis and Barrett’s esophagus Keywords: Barrett's Esophagus, esophagitis, adenocarcinoma, microbiome, inflammation

Esophageal adenocarcinoma is preceded by the development of reflux-related intestinal metaplasia or Barrett’s esophagus which is a response to inflammation of the esophageal squamous mucosa, reflux esophagitis. Gastroesophageal reflux impairs the mucosal barrier in the distal esophagus, allowing chronic exposure of the squamous epithelium to the diverse microbial ecosystem or microbiome, and inducing chronic inflammation. The esophageal microbiome is altered in both esophagitis and Barrett's esophagus, characterized by a significant decrease in Gram-positive bacteria and an increase in Gramnegative bacteria in esophagitis and Barrett's esophagus. Lipopolysaccharides (LPS), a major structure of the outer membrane in Gram-negative bacteria, can up-regulate gene expression of proinflammatory cytokines via activation of the TLR4 and NF-kB pathway. The potential impact of LPS on reflux esophagitis may be through relaxation of the lower esophageal sphincter via iNOS and by delaying gastric emptying via COX-2. Chronic inflammation may be play a critical role in the progression from benign to malignant esophageal disease. Therefore analysis of the pathways leading to chronic inflammation in the esophagus may help to identify biomarkers in Barrett's esophagus patients for neoplastic progression and provide insight into molecular events suitable for therapeutic intervention in prevention of esophageal adenocarcinoma development in patients with reflux esophagitis and Barrett's esophagus. Corresponding author: Zhiheng Pei, MD, PhD, FASCP Associate Professor of Pathology and Medicine New York University School of Medicine 423 East 23rd Street Room 6001W New York, NY 10010 Phone: 212-951-5492 Fax: 212-263-4108 Email: [email protected]